The emergence of bacteria that are highly resistant to conventional antibiotics, is a crisis in healthcare and has left clinicians squeezed between two opposing forces. The number of new antibiotics in the pharmaceutical pipeline has greatly diminished. Meanwhile, antibiotic resistance among bacterial pathogens is increasing at an alarming rate. Gram-negative bacteria such as Pseudomonas aeruginosa, Acinetobacter baumannii, and Klebsiella pneumoniae are especially problematic and have been designated “ESKAPE” pathogens because of their propensity to develop resistance to conventional antibiotics. Strategies are needed to treat these infections and address this crisis. Unfortunately, library screening for new classes of antibiotics has reached the point of diminishing returns, with frequent re-identification of already known drug classes. Approaches are required to provide new applications, and prolong the useful lifespan of conventional antibiotics.